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Therapy of Szary Syndrome


Joslyn S Kirby, Ellen J Kim, Alain H Rook Expert Rev Dermatol. 2009;4(6):567

Abstract and Introduction


Abstract

Szary syndrome (SS) is a lymphoma of skin-homing T cells. SS is defined as desquamative erythroderma involving at least 80% of the skin in addition to lymphadenopathy and leukemic involvement. Patients have a poor prognosis with an estimated 5-year survival of 2027% and estimated median survival of 1436 months. The goals of therapy are destruction of the malignant lymphocytes and correction of the immune imbalances caused by the malignant Th2 lymphocytes. Immunotherapeutics, such as interferons, retinoids, extracorporeal photopheresis and combination therapy are first-line therapies because of their favorable side-effect profiles. This review will focus on this interesting and expanding group of treatments. Chemotherapeutics, such as doxorubicin and gemcitabine, and monoclonal antibodies such as alemtuzumab, are second-line therapies owing to the risk of iatrogenic immunosuppression and cumulative toxicity. SS requires combination therapy, utilizing multiple skin-directed and systemic agents. The goal of this article is to discuss the treatment of SS, with a focus on immunotherapies
Introduction

Cutaneous T-cell lymphomas (CTCLs) are a diverse group of non-Hodgkin lymphomas caused by a malignant population of skin-trafficking T cells. Mycosis fungoides (MF) and Szary syndrome (SS) are the most common forms of CTCL and represent approximately 65% of the cases.[1] MF and especially SS are rare diseases with annual incidences in the USA of approximately 6.4 and 0.3 cases per million people, respectively.[2] The incidence has increased with time and may in part be due to improved clinical awareness and advances in diagnostic testing, as well as an increased number of new cases. The cause of most types of CTCL is unknown, with the exception of adult T-cell leukemia/lymphoma, which is caused by infection with human T-cell lymphotropic virus. Szary syndrome is defined by the WHO and European Organization of Research and Treatment of Cancer (EORTC) as desquamative erythroderma (erythema involving at least 80% of the skin surface), lymphadenopathy and leukemic involvement.[3] In addition to erythema, patients with SS will have a variable amount of scaling (Figure 1). Patients often report having chills and intolerable pruritus that interferes with sleep and other activities. Lymphadenopathy can be palpable or, in advanced cases, bulky and obvious on visual examination. Other manifestations of SS include alopecia, abnormalities of the finger and toe nails, thickening (keratoderma) and fissures of the skin of the palms and soles, and ectropion (eversion) of the lower lids.[4] The differential diagnosis includes pityriasis rubra pilaris, drug eruption or drug-induced pseudolymphoma, psoriasis, atopic dermatitis, contact dermatitis or photodermatitis, peripheral T-cell lymphoma and chronic lymphocytic leukemia. A single skin biopsy of erythroderma associated with SS is only diagnostic in approximately 50% of cases. More commonly it is nonspecific, demonstrating spongiosis, psoriasiform dermatitis, often with increased numbers of eosinophils, but small numbers of atypical lymphocytes.[5,6] Specific findings, such as Pautrier microabscesses, epidermotropism of atypical lymphocytes or dense aggregates of atypical lymphocytes in the dermis, are more common during patch/plaque stage MF.[58] Therefore, making the diagnosis of SS requires a combination of suggestive clinical examination results, consistent histologic findings and studies of the blood and/or lymph nodes.[7,9,10] Adjunctive studies include flow cytometry of the skin and blood, peripheral blood for Szary count (quantification of the large lymphocytes with cerebriform nuclei known as a Szary cell), PCR for clonal rearrangement of the T-cell receptor in the skin and/or blood and excisional lymph node biopsy.[7,912] In particular, flow cytometry of the peripheral blood is a sensitive test that can identify the malignant T cells by their loss of CD7 and CD26 antigens (which are present on normal T cells) even in the absence of clear lymphocytosis.[12] This method is used for both diagnosis and monitoring blood disease during and after therapy. The

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current staging system for MF and SS is the tumornodemetastasisblood (TNMB) classification and was updated in 2007 by the International Society for Cutaneous Lymphomas (ISCL) and EORTC.[3] The staging of cutaneous lymphomas, including CTCL, has evolved over time to reflect advances in our understanding of the disease. The current MF/SS staging system is detailed in & . Recently, the National Comprehensive Cancer Network (NCCN) published clinical practice guidelines for the diagnosis, staging and treatment of MF/SS, which are available online, under non-Hodgkin lymphomas and updated yearly.[201]
Table 1. TNMB stages of mycosis fungoides and Szary syndrome.

TNMB stage Skin (T) 1 2 3 4 Node (N) 0 1 2 3 X

Definition

Limited patches, papules and/or plaques covering <10% of the skin suface Patches, papules or plaques covering >10% of the skin surface One or more tumors (>1 cm diameter) Confluent erythema >80% body surface area

No clinically abnormal peripheral lymph nodes; biopsy not required Clinically abnormal peripheral lymph nodes; histologically Dutch grade 1 or NCI LN02 Clinically abnormal peripheral lymph nodes; histologically Dutch grade 2 or NCI LN3 Clinically abnormal peripheral lymph nodes; histologically Dutch grade 34 or NCI LN4 Clinically abnormal lymph nodes, no histological confirmation

Visceral/metastasis (M) 0 1 Blood (B) 0 1 2 Absence of significant blood involvement: >5% of peripheral blood lymphocytes are atypical (Szary) cells Low blood tumor burden: >5% of peripheral blood lymphocytes are atypical (Szary) cells High blood tumor burden: !1000 Szary cells per microliter with a positive clone No visceral organ involvement Visceral involvement (must have pathologic confirmation)

NCI: National Cancer Institute; TNMB: Tumornodemetastasisblood classification.


Table 2. International Society for Cutaneous Lymphomas/European Organization of Research and Treatment of Cancer updated staging of mycosis fungoides and Szary syndrome.

Stage Tumor Node Metastasis Blood IA IB II 1 2 12 0 0 1, 2 0 0 0 0, 1 0, 1 0, 1

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IIB III IIIA IIIB IVA1 IVA2 IVB

3 4 4 4 14 14 14

02 02 02 02 02 3 03

0 0 0 0 0 0 0

0, 1 0, 1 0 1 2 02 02

Figure 1.

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A typical patient with Szary syndrome and desquamative erythroderma. The prognosis of MF/SS correlates with the stage of disease; worse prognosis is associated with advanced disease in each organ (e.g., T1 vs T4 in the skin, B1 vs B2 for blood burden, N1 vs N3 in the lymph nodes) and with advanced clinical stage (combining organ systems; e.g., IA versus IIA).[13,14] Patients with limited patches of MF (T1) have an indolent disease that has no impact on their overall survival.[13] Patients with SS have advanced disease, evidenced by widespread skin disease, nodal and blood involvement. The 5-year survival for SS is approximately 2027% and median survival is approximately 14.536 months.[13,15] Older age at the time of presentation, elevated lactate dehydrogenase and eosinophilia are poor prognostic indicators.[16] SS patients not only have a higher risk of mortality, but their disease symptoms and the treatment side effects also cause a considerable degree of morbidity. The malignant cell in SS is typically a skin-homing Th2 (CD4+/CLA+/CCR4+/CD26") lymphocyte that produces a variety of soluble factors, including IL-4, IL-5, IL-10 and in some cases, TGF-# ( ). These factors result in eosinophilia, elevated IgE, impaired Th1 (cell-mediated) immunity, impaired dendritic cell (DC) and natural killer (NK) cell function and number, and may play a role in the loss of the normal T-cell repertoire ( ).[1719] In early patch stage MF, progression is limited by interferon-secreting host CD8+ cytotoxic T cells.[20] Decreased IFN-$, IL-12 and iatrogenic immunosuppression have been linked to disease progression.[21,22] The normal T-cell repertoire is greatly diminished in MF/SS patients, similar to advanced HIV infection.[19] Diminished T-cell repertoire probably results in impaired antimicrobial and anti-tumor surveillance and increased risk of secondary malignancies and life-threatening infections.[2325] Immunotherapy with interferons, retinoids, phototherapy extracorporeal photopheresis (ECP) and other agents can induce malignant T-cell apoptosis and thereby eliminate the malignant clone, and reestablish balance between Th1 and Th2 immunity, normalizing cellular immunity and avoiding the use of chemotherapeutics. It has been our experience that clearance of the circulating tumor cells has been uniformly associated with restoration of normal cellular immunity. The qualities of immunotherapuetics, anti-tumor effects and favorable side-effect profiles, make them first-line treatments and the focus of this review.
Box 1. Irregularities of the immune system in Szary syndrome.

% Th2 lymphocyte population & Th1 lymphocyte population % IL-4, 5, 10 & Cytotoxic (CD8+) lymphocytes and natural killer cells % Eosinophils & IL-12, 15, IFN-$ % IgE & Dendritic cell function and number & T-cell repertoire
Box 1. Irregularities of the immune system in Szary syndrome.

% Th2 lymphocyte population & Th1 lymphocyte population % IL-4, 5, 10 & Cytotoxic (CD8+) lymphocytes and natural killer cells % Eosinophils
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& IL-12, 15, IFN-$ % IgE & Dendritic cell function and number & T-cell repertoire In contrast to early MF, the treatment of SS must incorporate systemic treatments ( ) owing to the spread of malignant cells to the lymph nodes and blood. Skin-directed therapies ( ) are used to improve clinical response to systemic therapies and as palliation for pruritus ( ). Stage-based therapeutic guidelines are available (e.g., the NCCN guidelines for MF/SS have been available online since 2008); however, therapy is not formulaic and should take into account previous responses to therapy, comorbidities, and efficacy.[2628] Surprisingly, no treatment modality has been definitively shown to be curative or to improve survival, although multiple reports suggest improved survival with ECP alone or in combination.[29,30] Initial treatment of SS often consists of immunotherapies ( ), singly or in combination, because of their favorable side-effect profile, decreased risk of iatrogenic immunosuppression and lack of cumulative toxicity. Chemotherapeutics are considered for patients that have failed combination immunotherapy or have visceral disease. Single chemotherapy agents are attempted prior to multidrug regimens or stem cell transplantation (SCT). Patients that respond to either immunotherapy or chemotherapy are unlikely to maintain their response after cessation. Tapering dosage or maintenance treatment with an immunotherapeutic modality is recommended to prolong the duration of clinical response. Notably, unlike some malignancies that can become resistant to treatments, MF/SS may respond to previously successful therapies and thus repeat courses of the same therapy are common. Clinical trials and SCT are considerations for patients that are refractory or have contraindications to other therapies.
Table 3. Systemic therapies for Szary syndrome.

Agent Immunotherapy Retinoid/rexanoid RAR agonist (isotretinoin) RXR agonist (bexarotene)

Effect

Malignant cell apoptosis, % IFN-' Malignant cell apoptosis, & tumor IL-4 % IL-2R expression on malignant lymphocytes Enhanced Th1 immunity

Interferon (IFN-$, IFN-')

Inhibits malignant cell proliferation & Th2 cytokines (IL-4, -5 and -10)

Vorinostat (histone deacetylase inhibitor) Malignant cell apoptosis Malignant lymphocyte apoptosis ECP % DC recognition of lymphoma GM-CSF Other biologic therapy Denileukin diftitox Chemotherapy Methotrexate
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% DC number and function

Kills CD-25+ (IL-2R+) lymphocytes

Antiproliferative/antimetabolite
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Single agent Liposomal doxorubicin Gemcitibine Etoposide Chlorambucil Pentostatin Cyclophosamide Fludarabine Alemtuzumab Multiagent EPOCH CHOP Other Induction: cytotoxic Stem cell transplant Transplant: graft-versus-lymphoma effect CHOP: Cyclophosphamide, doxorubicin, vincristine and prednisone; DC: Dendritic cell; ECP: Extracorporeal photopheresis; EPOCH: Etoposide, prednisone, vincristine, cyclosporine and doxorubicin; GM-CSF: Granulocyte macrophage colony-stimulating factor; IL-2R: IL-2 receptor; RAR: Retinoic acid receptor; RXR: Retinoid X receptor.
Table 4. Skin-directed therapies.

Cytotoxic Cytotoxic Cytotoxic Cytotoxic T-cell inhibitory/depleting Cytotoxic Cytotoxic Kills CD-52+ lymphocytes

Cytotoxic Cytotoxic

Agent Topical

Effect

Malignant lymphocyte apoptosis Corticosteroids & LC in skin Nitrogen-mustard (mechlorethamine) or carmustine Cytotoxic Retinoid/rexanoid Light therapy Malignant lymphocyte apoptosis Narrow-band UVB & LC in skin Malignant lymphocyte apoptosis Psoralens with UVA (PUVA) & LC in skin Radiation therapy Total skin electron beam Localized electron beam
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Malignant lymphocyte apoptosis (see Table 3)

Malignant lymphocyte apoptosis Malignant lymphocyte apoptosis


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Table 5. Palliative therapies.

Agent Topical Corticosteroids Pramoxine, menthol Bleach bath Antibiotics (e.g., mupirocin, bacitracin) Systemic

Effect

Antipruritic, anti-inflammatory Anesthetic, antipruritic Antibacterial Antibacterial

Antihistamines (e.g., diphenhydramine, hydroxyzine, doxepin) Antipruritic, sedative Gabapentin Mirtazipine Antibiotics (e.g., doxycycline, cephalexin) Corticosteroids
Table 3. Systemic therapies for Szary syndrome.

Antipruritic Antipruritic Antibacterial Antipruritic, anti-inflammatory

Agent Immunotherapy Retinoid/rexanoid RAR agonist (isotretinoin) RXR agonist (bexarotene)

Effect

Malignant cell apoptosis, % IFN-' Malignant cell apoptosis, & tumor IL-4 % IL-2R expression on malignant lymphocytes Enhanced Th1 immunity

Interferon (IFN-$, IFN-')

Inhibits malignant cell proliferation & Th2 cytokines (IL-4, -5 and -10)

Vorinostat (histone deacetylase inhibitor) Malignant cell apoptosis Malignant lymphocyte apoptosis ECP % DC recognition of lymphoma GM-CSF Other biologic therapy Denileukin diftitox Chemotherapy Methotrexate Single agent Liposomal doxorubicin
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% DC number and function

Kills CD-25+ (IL-2R+) lymphocytes

Antiproliferative/antimetabolite

Cytotoxic
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Gemcitibine Etoposide Chlorambucil Pentostatin Cyclophosamide Fludarabine Alemtuzumab Multiagent EPOCH CHOP Other

Cytotoxic Cytotoxic Cytotoxic T-cell inhibitory/depleting Cytotoxic Cytotoxic Kills CD-52+ lymphocytes

Cytotoxic Cytotoxic

Induction: cytotoxic Stem cell transplant Transplant: graft-versus-lymphoma effect CHOP: Cyclophosphamide, doxorubicin, vincristine and prednisone; DC: Dendritic cell; ECP: Extracorporeal photopheresis; EPOCH: Etoposide, prednisone, vincristine, cyclosporine and doxorubicin; GM-CSF: Granulocyte macrophage colony-stimulating factor; IL-2R: IL-2 receptor; RAR: Retinoic acid receptor; RXR: Retinoid X receptor.

Immunotherapy
Immunotherapies () can have a myriad of effects on the malignant lymphocyte and on the lymphoma-suppressed immune response, which is important to limit infections and secondary malignancies. Similar to combination chemotherapeutics, the principle of using combination immunotherapies is to enhance the overall effect by utilizing therapies with different but complimentary antiproliferative effects and limit toxicity from individual drugs. Specific combination therapies will be discussed later, but the common goals are to induce apoptosis of malignant lymphocytes, encourage DC processing and presentation of lymphoma cells, increase cytotoxic (CD8+) lymphocyte function and killing of malignant T cells, and support a shift from Th2 to Th1 cytokine production.[17]
Table 3. Systemic therapies for Szary syndrome.

Agent Immunotherapy Retinoid/rexanoid RAR agonist (isotretinoin) RXR agonist (bexarotene)

Effect

Malignant cell apoptosis, % IFN-' Malignant cell apoptosis, & tumor IL-4 % IL-2R expression on malignant lymphocytes Enhanced Th1 immunity

Interferon (IFN-$, IFN-')

Inhibits malignant cell proliferation & Th2 cytokines (IL-4, -5 and -10)

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Vorinostat (histone deacetylase inhibitor) Malignant cell apoptosis Malignant lymphocyte apoptosis ECP % DC recognition of lymphoma GM-CSF Other biologic therapy Denileukin diftitox Chemotherapy Methotrexate Single agent Liposomal doxorubicin Gemcitibine Etoposide Chlorambucil Pentostatin Cyclophosamide Fludarabine Alemtuzumab Multiagent EPOCH CHOP Other Induction: cytotoxic Stem cell transplant Transplant: graft-versus-lymphoma effect CHOP: Cyclophosphamide, doxorubicin, vincristine and prednisone; DC: Dendritic cell; ECP: Extracorporeal photopheresis; EPOCH: Etoposide, prednisone, vincristine, cyclosporine and doxorubicin; GM-CSF: Granulocyte macrophage colony-stimulating factor; IL-2R: IL-2 receptor; RAR: Retinoic acid receptor; RXR: Retinoid X receptor. Cytotoxic Cytotoxic Cytotoxic Cytotoxic Cytotoxic Cytotoxic T-cell inhibitory/depleting Cytotoxic Cytotoxic Kills CD-52+ lymphocytes Antiproliferative/antimetabolite Kills CD-25+ (IL-2R+) lymphocytes % DC number and function

Extracorporeal Photophoresis
Extracorporeal photopheresis was introduced as a therapy for CTCL in early 1980s by Edelson and approved by the US FDA in 1988.[31] It is considered by many to be first-line therapy for SS. During ECP, whole blood is removed from the patient (225 ml or 0.47 pints); the buffy coat containing the leukocytes is separated and extracorporeally combined with 8-methoxypsoralen, a photosensitizer, then exposed to UVA light and infused back into the patient. The remaining portion of the blood, including red blood cells, is reinfused.[32,33] ECP is typically performed on two consecutive days every month. The frequency of treatment can be increased for resistant cases and alternative protocols have also been used.[34] A patient should be treated for at least 69 months before ECP is considered a therapeutic failure. ECP is a specialized treatment and not widely available; patients often travel some distance to large medical centers where the equipment is available. Adverse effects are uncommon but include transient hypotension, low-grade fever,
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transiently increased cutaneous erythema and anemia due to incomplete red blood cell return after separation. Contraindications include coagulation abnormalities, allergy to methoxypsoralen and advanced heart, hepatic or renal disease because of intolerance to alterations in blood volume. Initially, ECP was thought to primarily debulk the atypical lymphocytes in the blood; however, only 25% of lymphocytes are exposed to the 8-methoxypsoralen. An additional effect, aside from reduction of circulating malignant T-cells, is an immunomodulatory effect on Th1/Th2 cytokine production and enhanced DC processing of malignant cells.[35,36] DCs are integral to immune recognition of malignant lymphocytes via MHC presentation of stem cell antigens and destruction by CD8+ lymphocytes.[37] The overall response rate (OR) of ECP is 5383% and the complete response rate (CR) is 826% and varies based on treatment protocol, prior therapies, additional adjuvant therapies and duration of disease.[38,39] Potential adjuvant therapies include IFN-$, IFN-', bexarotene, and granulocytemacrophage colony-stimulating factor (GM-CSF).[40]

Interferon
Interferons are a family of glycoproteins with a myriad of biological effects, including antiproliferative and immunoregulatory effects.[41] In the therapy of SS these effects include inhibition of Th2 cytokine production, inhibition of stem cell growth and improvement of cell-mediated cytotoxicity.[41] IFN-$2a and 2b are biologically similar, differ by only one amino acid and have been used to treat MF and SS. Interferon is dosed per million units (MU) and is typically administered by subcutaneous injection that yields at least 80% absorption. Previous reviews have demonstrated similar response rates for IFN-$2a and 2b.[42,43] IFN-$ is commonly administered as a 39-MU dose subcutaneously three-times weekly to daily.[43] A review by Bunn et al. of IFN-$ for MF and SS found an OR of 55% and CR of 17%. There was no analysis of patients with advanced disease (SS). Olsen et al. and Papa et al. reported an OR of 60 and 70%, respectively, for patients with stage III and IV disease treated with IFN-$.[44,45] Higher dose regimens (>10 MU/day)may result in better response rates than low-dose regimens (35 MU daily or three-times weekly); however, this was not statistically significant in one study.[45,46] The use of high-dose regimens is often limited by intolerance of adverse effects, but low-dose regimens are generally well tolerated. The most common side effects include fever, chills, arthralgias, myalgias and malaise. These effects are dose-dependent and improve with acetaminophen and continued therapy. Patients with worsening constitutional symptoms after prolonged interferon (IFN) therapy should be evaluated for infection and not have their symptoms ascribed to treatment.[43] Additional dose-dependent side effects include anorexia, weight loss, depression, decrease in cognitive function and memory, motor dysfunction, peripheral neuropathy, psychosis, hair thinning, changes in sexual function and, rarely, autoimmune phenomena (thyroiditis, nephritis, psoriasis). Myelosuppression and transaminitis can occur at doses used to treat SS, but rarely necessitates cessation of therapy. IFN-$ is also available in a pegylated form that has a longer half-life, requiring only once weekly administration, which is particularly useful for children who may have a fear of injections. IFN-' has no homology to IFN-$ and is a useful alternative for cases refractory to IFN-$.[47] IFN-' can increase DC function and IL-12 production, both of which are important to normalization of immunity and reduction in the malignant cell population.[22] IFN-' therapy is started at 50 (g (half a vial) three-times per week and increased as tolerated to 100 (g three- to five-times per week. IFN-' is typically better tolerated than IFN-$, particularly among the elderly. IFN-' appears to be associated with a lower incidence of depression or other cognitive disorders. IFN-$ or -' can be combined together or with one or more of the following treatments: ECP, bexarotene, methotrexate, denileukin diftitox, or skin-directed therapies (e.g., phototherapy, electron beam radiation therapy).

Retinoids
Retinoids are a group of synthetic and natural chemicals that mimic the effects of vitamin A. Retinoids bind one of two families of receptors known as the retinoic acid receptor and retinoid X receptor. The receptors are found in the nucleus and function as transcription factors influencing transcription of genes involved in inflammation, cellular differentiation and apoptosis.[48] Bexarotene, the first retinoid X receptor-specific oral retinoid to be studied in humans, is approved for the treatment of CTCL and has been studied most extensively for MF.[49,50] Guidelines have been published on the use of bexarotene for CTCL.[51,52] Bexarotene is administered daily at a dose of 150 mg/m2 and increased to 300 mg/m2 as tolerated. Dose escalation is encouraged since efficacy is dose-related. The most common
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toxicities are dose-dependent hypertriglyceridemia and central hypothyroidism. Most patients will develop these side effects so it is recommended that thay should start fenofibrate 160 mg daily or a statin for 1 week prior to, and levothyroxine 25 (g daily at the start of, bexarotene therapy. Niacin or omega-3 fatty acids can be added if additional reduction of triglycerides or cholesterol is needed. Gemfibrozil, another fibrate, is contraindicated because it can increase bexarotene levels by inhibition of hepatic CYP3A4 enzymes. Laboratory monitoring of lipids and thyroid function, including serum free T4 and total T4 should be done at baseline and every month. Thyroid-stimulating hormone production is suppressed by bexarotene and results in a hypothyroid-state. To the untrained eye, this thyroidstimulating hormone suppression would suggest hyperthyroidism; hence the importance of monitoring free and total T4. Abbott et al. reported their experience with bexarotene for CTCL.[53] In total, 24 SS patients were treated and the OR was 75%. Seven SS patients (41%) had clearance of their blood involvement; one received bexarotene monotherapy and the remainder received combination therapy. Bexarotene has been combined with IFN-$, IFN-', phototherapy, denileukin diftitox, vorinostat and ECP to increase clinical response. Etretinate, all-trans-retinoic acid and 13-cis-retinoic acid have also been used to treat CTCL. These retinoids are used less frequently because of their limited availability, short duration of action and limited number of patients treated.[54] In 120 CTCL patients treated with these drugs, the OR was 58% and CR 19%.[42] Retinoic acid receptor agonists are capable of augmenting IFN-' production, which makes them potentially useful in multimodality therapy with IFN.[5558] Acitretin is infrequently reported as a treatment for CTCL, most cases had disease limited to the skin so the effect on extracutaneous disease is not known.[5961]

Histone Deacetylase Inhibitors


Vorinostat, an oral agent, is the first FDA-approved drug in a novel class of medications known as histone deacetylase (HDAC) inhibitors. The degree of histone acetylation influences the coiling of DNA and hence the availability of genes for transcription.[62] HDAC inhibitors have been shown to have inhibitory effects on multiple types of malignancies, including CTCL. These drugs not only affect gene expression via histone acetylation but also interact with transcription factors, DNA repair enzymes and structural proteins.[63,64] HDAC inhibitors not only have anti-tumor effects but have also been shown to increase Foxp3+ Tregs and mediators of inflammation.[64,65] In two Phase II clinical studies, patients with SS had an OR of 33 and 36% with improvement in skin, nodal and blood disease.[66,67] No patient achieved a CR. Vorinostat had only a modest effect on heavily pretreated SS patients, but did demonstrate an impressive antipruritic effect, which has implications for quality of life. Relief of pruritus was noted in not only those with mild pruritus scores but also 4359% of those with severe pruritus (>7 out of 10). The effect on pruritus is rapid, with a median time to effect of 16 days; earlier than the median time to clinical response of the skin lesions (5556 days). An advantage of vorinostat is the ease of oral administration; the FDA-approved dose is 400 mg daily, given as four 100 mg pills. Common side effects include diarrhea, fatigue, nausea and anorexia, but rarely required cessation of therapy. More severe side effects, such as pulmonary embolism and thrombocytopenia, were uncommon ()5%). Multimodality treatment with vorinostat and bexarotene as well as vorinostat and IFN-' has been studied.[68,69] Also, in vitro studies suggest the effects of vorinostat on DNA coiling may make the malignant T cells more susceptible to the effects of radiation and chemotherapy.[63]

Other Biologic Therapy


Immunotoxin

Denileukin diftitox is a fusion protein of IL-2 and diphtheria toxin. It is FDA-approved for the treatment of recurrent or persistent CTCL whose malignant cells express the CD25 component of the IL-2 receptor. The drug binds to the intermediate and high affinity IL-2 (CD25+) receptors (IL-2R) found primarily on macrophages, NKs, activated T and B lymphocytes and atypical lymphocytes in CTCL. The drug is endocytosed and once inside the cell the toxin portion inhibits protein synthesis resulting in cell death.[70] The drug is administered intravenously; a typical course consists of daily infusions for 5 days and can be repeated every 21 days. A Phase III study investigated two doses, 9 and 18 (g/kg/day with an OR of 30% and CR of 10% for all subjects.[71] Responses were not dose dependent, although there

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was a trend towards greater responses among those who received the higher dose. Three patients with Stage IV CTCL had a response (two partial responses and one clinical complete response). The total number of stage IV patients treated was not reported. The soluble form of the IL-2R is found at particularly high levels in SS patients with a high burden of circulating cells and has been shown to correlate with disease burden and prognosis.[72] High levels of the soluble form of IL-2R may act as a sink, binding the fusion protein so it is unavailable to bind the IL-2R on the malignant lymphocyte, resulting in diminished effect. The side effects of this treatment make it less commonly used. The major side effects are a vascular leak syndrome (VLS) and infusion/hypersensitivity reactions which occurred in 25 and 60% of subjects in the Phase III study, respectively. VLS usually developed in the first 2 weeks after each treatment course. The exact etiology of VLS is unknown but may be due to dehydration, hypoalbuminemia and/or increased capillary permeability. Caution should be used if considering treatment of patients with heart, kidney or liver disease that cannot tolerate changes in volume status. Daily weights, extremity edema, blood pressure and serum albumin levels should be monitored during therapy. The infusion/hypersensitivity reaction includes symptoms of sudden back or chest pain, hypotension, dyspnea, angioedema, pruritus and/or a rash around the time of infusion. Although not administered as part of the Phase III trial, it is a common practice to administer an intravenous dose of corticosteroid, such as dexamethasone or methylprednisolone prior to or concomitant to the drug infusion to lessen these symptoms. Decreasing the rate of infusion and preadministration of NSAIDs and/or antihistamines can also ameliorate the symptoms. Additional less common side effects include thrombotic events, vision changes and cytopenias, including thrombocytopenia, neutropenia and leukopenia. Lymphopenia (<1000 cells/(l) occurred in 70% of subjects, but 24% of subjects were lymphopenic at baseline and no adverse event or treatment interruption occurred. In vitro studies demonstrated increased expression of the IL-2 receptor on leukemic lymphocytes treated with bexarotene, prompting the use of this combination in a small number of patients.[73,74] Multimodality therapy of denileukin diftitox (18 (g/kg) and bexarotene (!150 mg) has been studied in a Phase I trial. The OR and CR improved to 67 and 28%, respectively.[74]

Chemokine
Sargramostim or GM-CSF is a potent stimulant of hematopoiesis but has also demonstrated effects against malignancies such as CTCL, melanoma, leukemia and breast cancer.[75] Bouwhis et al. first reported the use of GMCSF as an adjuvant to multimodality therapy for SS. The patient had a complete response of his blood involvement and partial improvement of his cutaneous disease. Sargramostim is also used by our group as an adjuvant to multimodality therapy for recalcitrant SS.[30,40] The use of GM-CSF as an adjuvant to ECP is biologically plausible because it increases DC number and function, which is a key component of the immunoregulatory effects of ECP.[30,40,75]

Combination Biologics
Systemic therapies are combined for two main reasons; to enhance the quantity and quality of response rates and to limit toxicity. Most studies of CTCL assess the outcomes of monotherapy; fewer studies with fewer patients have assessed multimodality therapy. Several reviews discuss the utility of combination therapy.[26,40,7678] Several combination therapies are highlighted below. Multimodality therapy utilizing at least three therapies, ECP and a combination of two or more other immunotherapies (IFN-$, IFN-', bexarotene, GM-CSF) was retrospectively studied in 28 patients with SS.[30] The results, an OR of 89 and CR of 29%, exemplify the potential benefits of multimodality therapy. Similar successful reports (mostly retrospective studies) utilizing the combination of ECP, bexarotene and IFN-$ or IFN-' have been published by this group and others.[40,47,53] A summary of the trails using combination biologics is given in the following list: Vorinostat and bexarotene: a Phase I trial of comparing multiple regimens of vorinostat with bexarotene, 18 evaluable patients including nine with stage IV disease has so far resulted in an OR of 22% and a CR of 5%, and is still accruing patients;[68] Vorinostat and IFN-': three patients with SS were treated with vorinostat and IFN-' and yielded an OR of
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100%, but none had a CR;[69] Denileukin diftitox and bexarotene: the combination of denileukin diftitox (18 (g/kg) and bexarotene (!150 mg) was studied in a Phase I trial. The OR and CR were 67 and 28%, respectively. Three patients had stage IV disease; two patients were evaluable and neither had a response to treatment;[74] ECP and bexarotene: two patients with SS treated with standard regimen ECP and bexarotene (300 mg/m2).[79] One patient had a CR in the skin but no change in blood burden of disease. The second patient had a partial response of both cutaneous and blood disease. The combination of bexarotene with ECP requires careful monitoring of serum lipids the hypertriglyceridemia typically associated with bexarotene, can interfere with the ability of the machine to discern the buffy coat from blood fats; ECP and IFN: Dippel et al. treated 19 patients with advanced CTCL, 10 patients (two SS) received ECP alone and nine patients (one SS) received ECP with IFN-$ (318 MU three-times weekly). None of the three SS patients responded.[80] For all subjects, ECP alone yielded an OR of 20% and CR of 10%, while ECP and IFN improved OR to 60% and CR to 40%. Gottlieb et al. studied ECP with IFN-$ (1.55 MU 35-times weekly) in 31 patients with CTCL.[29] The OR was 71% and CR was 25%. In total, 27 of the patients had leukemic involvement. In this population, seven patients had a CR (26%) and 20 had some response (OR = 74%). An earlier study combined IFN-$ (320 MU three-times weekly) and ECP to treat six patients with SS.[46] The OR was 66%. No patient had a CR. A dose response with IFN-$ was suggested; IFN and bexarotene: eight patients with SS were treated with bexarotene (300 mg/m2) and IFN-$ (3 MU threetimes weekly) for 8 weeks.[81] The OR was 37% and no patient obtained a CR.

Chemotherapy
Single-agent chemotherapies as well as combination chemotherapies () are generally reserved for patients refractory to combination immunotherapy or those with bulky lymphadenopathy or visceral involvement. Recent reviews address the use of conventional chemotherapeutics, such as liposomal doxorubicin, gemcitabine and others.[26,28] ORs range from 16 to 70%.[28] Complete responses occur in 2025% of these heavily pretreated patients. Time to response is shorter than immunotherapies, but relapse is also rapid with responses maintained for 36 months. Toxicity from chemotherapeutics is frequent and is episodic during therapy (cytopenias) or cumulative (neurotoxicity, cardiomyopathy). Single-agent therapy is often attempted prior to combination therapies to limit toxicity and cumulative dosages.
Table 3. Systemic therapies for Szary syndrome.

Agent Immunotherapy Retinoid/rexanoid RAR agonist (isotretinoin) RXR agonist (bexarotene)

Effect

Malignant cell apoptosis, % IFN-' Malignant cell apoptosis, & tumor IL-4 % IL-2R expression on malignant lymphocytes Enhanced Th1 immunity

Interferon (IFN-$, IFN-')

Inhibits malignant cell proliferation & Th2 cytokines (IL-4, -5 and -10)

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Vorinostat (histone deacetylase inhibitor) Malignant cell apoptosis Malignant lymphocyte apoptosis ECP % DC recognition of lymphoma GM-CSF Other biologic therapy Denileukin diftitox Chemotherapy Methotrexate Single agent Liposomal doxorubicin Gemcitibine Etoposide Chlorambucil Pentostatin Cyclophosamide Fludarabine Alemtuzumab Multiagent EPOCH CHOP Other Induction: cytotoxic Stem cell transplant Transplant: graft-versus-lymphoma effect CHOP: Cyclophosphamide, doxorubicin, vincristine and prednisone; DC: Dendritic cell; ECP: Extracorporeal photopheresis; EPOCH: Etoposide, prednisone, vincristine, cyclosporine and doxorubicin; GM-CSF: Granulocyte macrophage colony-stimulating factor; IL-2R: IL-2 receptor; RAR: Retinoic acid receptor; RXR: Retinoid X receptor. Methotrexate (MTX), a folate antagonist, is sometimes not thought of as a conventional chemotherapeutic; however, it has both antiproliferative and immunosuppressive effects.[82] It is discussed here briefly because it is both widely available and commonly used to treat MF/SS. Zackheim et al. reviewed their experience with MTX treatment of SS and MF.[83,84] For 29 patients with SS, MTX was usually administered weekly and the dose ranged from 5 to 125 mg. Doses less than 25 mg (ten patients) were administered orally while doses exceeding 25 mg (19 patients) were given by injection. The OR and CR for this study were 58 and 41%, respectively. Side effects included transaminitis (eight patients), oral and/or cutaneous erosions (12 patients), nausea and/or diarrhea (11 patients), leukopenia or thrombocytopenia (three patients) and pulmonary fibrosis (two patients). MTX has also been studied in combination with IFN-$; MTX (10 mg/m2 twice weekly) and IFN-$ (9 MU three-times weekly) were used to treat 158 patients with advanced-stage (IIB or higher) CTCL.[85] At 6 and 12 months, the CR was 31 and 49%, respectively. Patients were given the combination treatment until CR then given maintenance therapy with IFN. If disease recurred combination
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% DC number and function

Kills CD-25+ (IL-2R+) lymphocytes

Antiproliferative/antimetabolite

Cytotoxic Cytotoxic Cytotoxic Cytotoxic T-cell inhibitory/depleting Cytotoxic Cytotoxic Kills CD-52+ lymphocytes

Cytotoxic Cytotoxic

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therapy was reinstituted. The number of patients and outcomes for SS patients specifically was not discussed. Chlorambucil, like cyclophosphamide, is an alkylating agent and is derived from nitrogen mustard. It is commonly administered in conjunction with a corticosteroid; this combination is also known as the 'Winkelmann regimen' and has been used to treat advanced CTCL including SS.[8688] In 1989, Winkelmann et al. reviewed their experience with this regimen. A total of 40 patients with SS were treated with a standard dose of chlorambucil 4 mg daily and prednisone 20 mg daily. Once erythrodermic patients treated with the Winkelmann regimen lived twice as long as those treated otherwise. Of patients on long term therapy, seven (37%) out of 19 had a complete response for at least 1 year and ten (59%) out of 17 had a significant decline in peripheral stem cells. Chlorambucil with corticosteroid for SS has also been administered in twice-monthly pulses, similar to that used for chronic lymphocytic leukemia.[88] Higher doses are given for fewer days with the hope that cumulative doses are lower. Coors et al. utilized this pulsed regimen for 13 patients with SS and an OR of 100% and a CR of 54%. Both reports noted improvement in pruritus at 13 months with improvement in clinical examination taking longer (36 months). The most common main side effect was leukopenia. Other side effects were carcinogenicity, seizures and infertility. The Winkelmann regimen has also been modified to include ECP.[89] Another agent that widely ablates immune cells similar to conventional chemotherapy is alemtuzumab, an anti-CD52, humanized IgG monoclonal antibody. CD52 is a highly expressed glycoprotein found on normal and malignant B and T lymphocytes, as well as NK cells. In vitro, alemtuzumab induces complement- and antibody-dependent cellular cytotoxicity, as well as direct apoptosis of the malignant T cells.[90] The standard therapeutic schedule calls for intravenous administration of escalating doses to 30 mg three-times a week for 12 weeks.[91] At these doses there is a profound and long-lasting depletion of mature B and T lymphocytes, which contributes to the prevalence of grade 3/4 infectious events and hematologic toxicity. Alternative dosing schedules combining lower doses and subcutaneous administration have been shown to preserve the efficacy of this agent, reduce the number of infectious complications and eliminate infusion reactions.[92,93] Small studies of its use for SS have shown excellent results with CRs between 32 and 47%. In the largest series of patients with advanced MF/SS reported, alemtuzumab administered at the standard (higher dose) schedule resulted in an OR of 65% and a CR of 32%; median pruritus scores decreased from eight to two (out of ten).[94] An alternative low-dose regimen of subcutaneous alemtuzumab therapy resulted in an OR of 86% (12 out of 14), CR in 21%, reduced median pruritus scored from nine to three (out of 10), and reduced the frequency of infections.[92] With high-dose regimens infectious complications have been both highly prevalent and dangerous. In studies of alemtuzumab for nodal lymphomas, 2379% of patients developed an infection. The most common infections are reactivation of herpes family viruses (EpsteinBarr virus and cytomegalovirus); however, bacterial sepsis, atypical mycobacterial and fungal infections also occurred. Prophylaxis with trimethoprim/sulfamethoxazole and valacyclovir, with or without voriconazole has been advocated. Hematologic toxicity is also common; cytopenias (at least grade 2) occurred in up to 46%.[91] Monitoring of blood counts, cytomegalovirus, EpsteinBarr virus and Szary counts should be considered during treatment. The side effects and profound suppression of malignant and normal lymphocytes make alemtuzumab very similar to conventional chemotherapeutics; however, early studies demonstrate better response rates.

Stem Cell Transplantation


Stem cell transplantation has been used in a small proportion of patients with advanced and/or refractory CTCL. The benefit of the allogeneic transplant includes not only the massive reduction in tumor burden by the chemotherapeutic conditioning regimen, but also the sustained graft-versus-lymphoma (GVL) effect of the graft. The malignant lymphocytes of the host are seen as 'nonself' by the graft and killed. Therefore, it is not surprising that autologous SCT has not demonstrated durable remissions since there is no GVL effect.[9597] Modifications in conditioning regimens, such as nonmyeloablative or reduced-intensity regimens, can limit early toxicity and mortality; making SCT a safer option for older patients and those with comorbidities.[9799] A review by Introcaso et al. demonstrated that if the patient can survive the early transplant period then there is a reasonable chance of a durable CR.[100] In this review, 14 of 17 patients survived and went into remission (CR 82%). Three patients (18%) died due to infections following transplantation; this is within the range of published mortality rates for allogeneic SCT for other indications.[101] The
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goal of SCT for SS is to balance the benefit of the GVL effect against the detriment of graft-versus-host disease (GVHD). Most SCT patients will develop GVHD and the extent can be limited or generalized; treatment is immunosuppression. Various ECP regimens have also been found to be quite effective for GVHD and provide steroidsparing effects. Some patients feel they trade one chronic disease for another. Lymphoma relapse after allogeneic SCT can be treated with a donor lymphocyte infusion to augment GVL effect.

Skin-directed Therapy
Skin-directed therapy ( & should always be a part of the treatment regimen and can be remissive or palliative. Both psoralen with UVA (PUVA) phototherapy and total skin electron beam (TSEB) have the capacity to clear the skin with the latter being substantially more potent. A recent case series established that TSEB administered to SS patients on a stable regimen of ECP, interferon and bexarotene could clear not only the skin but the blood as well.[102] Skindirected therapy (including topical emollients, corticosteroids, retinoids, compounded nitrogen mustard or carmustine) is also important for the considerable pruritus that can accompany SS and can lead to scratching and portals of entry for bacteria. Erythrodermic patients have been shown to harbor Staphylococcus aureus and treatment of colonization correlates with clinical improvement.[103] In addition to their abnormal skin barrier and colonization, the lymphomainduced immune imbalance and diminished cytotoxic response contribute to an increased risk of cutaneous and systemic infections, which are a source of morbidity and mortality.[24] Cutaneous infections with bacteria or herpes simplex virus are common and can become disseminated. In a series by Axelrod et al., the majority of SS patients died of infections; pneumonia and bacteremia were the cause of death in 88% of these patients.[24] Notably, the presence of extracutaneous disease (e.g., SS and visceral involvement) was the most important risk factor for cutaneous and systemic infections. Pruritus also has an effect on quality of life. Multiple studies have demonstrated negative effects on scores of emotional health (e.g., frustration, fear), physical functioning (e.g., ability to perform at work or hobbies) and social wellbeing (e.g., visibility of rash, depression) due to skin symptoms (e.g., pruritus, pain).[104106]
Table 4. Skin-directed therapies.

Agent Topical

Effect

Malignant lymphocyte apoptosis Corticosteroids & LC in skin Nitrogen-mustard (mechlorethamine) or carmustine Cytotoxic Retinoid/rexanoid Light therapy Malignant lymphocyte apoptosis Narrow-band UVB & LC in skin Malignant lymphocyte apoptosis Psoralens with UVA (PUVA) & LC in skin Radiation therapy Total skin electron beam Localized electron beam Malignant lymphocyte apoptosis Malignant lymphocyte apoptosis Malignant lymphocyte apoptosis (see Table 3)

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Table 5. Palliative therapies.

Agent Topical Corticosteroids Pramoxine, menthol Bleach bath Antibiotics (e.g., mupirocin, bacitracin) Systemic

Effect

Antipruritic, anti-inflammatory Anesthetic, antipruritic Antibacterial Antibacterial

Antihistamines (e.g., diphenhydramine, hydroxyzine, doxepin) Antipruritic, sedative Gabapentin Mirtazipine Antibiotics (e.g., doxycycline, cephalexin) Corticosteroids Antipruritic Antipruritic Antibacterial Antipruritic, anti-inflammatory

In summary, the treatment of SS is not standardized, but multiple guidelines have been published.[2628] The most common course of disease for SS is one of multiple remissions and relapses. No treatment modality has been shown to markedly alter the course of the disease, which has a median survival of approximately 14.536 months.[13] The principles of treatment are to limit toxicity, maintain immune function, reduce tumor burden, correct immune imbalance and improve quality of life. Treatment toxicity in the form of immunosuppression and cytopenias are especially problematic for this population due to limited T-cell repertoire and reduced cytotoxic immune response.[17] Multimodality therapy with both skin-directed and one or more systemic agents should be utilized to reduce the burden of disease, control pruritus, limit infection and minimize treatment side effects.

Expert Commentary
Szary syndrome is a rare and intriguing lymphoma of skin-homing T cells. Unlike other non-Hodgkin lymphomas, first-line treatment for SS is not polychemotherapy or SCT. However, this should not be misconstrued to mean that SS is any less serious a malignancy; the median survival ranges from only 14.536 months. ECP, a first-line therapy, was developed as a means to treat the leukemic spread of the malignant cells with the same therapeutic principles of PUVA phototherapy for the mycosis fungoides subtype of CTCL. This ingenious therapy has been used as a first-line therapy since its development over 20 years ago yet the mechanisms of its effects are not completely understood. It was initially thought to debulk the circulating malignant cells; however, it is now known that fewer than 5% of the circulating malignant T cells are affected. The more likely explanation for SS improvement by ECP is via stimulation of immune system destruction of the malignant lymphocytes. SS is a malignancy of immune cells that can be managed by exploiting other aspects of the immune system. This article touches on several of the therapeutic options that harness the antineoplastic immune response (immunotherapies) and avoid the toxicity of chemotherapy. The OR and CR of individual immunotherapies are modest in some cases; however, to put this in perspective, the patients receiving these drugs in clinical trials have often failed two or more other therapies. Also, the likelihood of achieving an overall or complete response can be substantially improved by combining two or more immunotherapies. Treatment decisions should include the likelihood to induce a response or remission, side effects, possibility for combination therapy, patient comorbidities and cost/availability of the modality. Our favored first-line therapy for SS is ECP, bexarotene and IFN-$; with the substitution of IFN-' if there is not sufficient improvement. This regimen is effective and well-tolerated in many patients. Additional therapies that may be added to this combination regimen include skindirected therapies such as PUVA, TSEB and other systemic immunomodulatory agents such as GM-CSF. This

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combination immunomodulatory approach is also often used as maintenance therapy to sustain responses. Clinical trials can be considered for patients with refractory disease as there are many promising therapeutics that are being developed (see 'Five-year view').

Five-year View
Research continues to illuminate the intricacies of the immune system and its associated disease states, particulary in SS. The early success of immunotherapies, such ECP, retinoids and cytokines, has triggered further research of additional therapies and combination therapies. Romidepsin (depsipeptide) and panobinostat are HDAC inhibitors currently in clinical trials, while vorinostat is currently FDA approved. Resiquimod and CpG oligodeoxynucleotides are systemic Toll-like receptor agonists in development, while imiquimod, a topical Toll-like receptor agonist, is already available for use. Additional immunotoxins are also being developed, similar to denileukin diftitox. LMB-2 is a fusion protein combining Pseudomonas exotoxin and a monoclonal antibody against CD-25. Additional areas of research include chemokine (e.g., CCR4) antagonists, transition-state inhibitors such as forodesine, serine-tyrosine kinase inhibitors such as enzastaurin, monoclonal antibodies directed against CD4+ T-cells (zanolimumab) and new conditioning regimens for SCT.

Sidebar
Key Issues

Szary syndrome (SS) is classically defined as the triad of desquamative erythroderma involving at least 80% of the skin surface, lymphadenopathy and leukemic involvement. Patients with SS have advanced disease with a 5-year survival of approximately 2027% and estimated median survival of 1436 months. The malignant cell in SS is typically a skin-homing Th2 (CD4+/CLA+/CCR4+/CD26") lymphocyte, which results in immune imbalances, such as: Elevated amounts of IL-4, -5 and -10; Eosinophilia and elevated IgE; Impaired Th1 (cell-mediated) immunity and dendritic cell function and number; Loss of the normal T-cell repertoire. Treatment principles include: Combine immunotherapies to improve efficacy and limit toxicity from individual agents; Avoid iatrogenic immunosuppression; Combine skin-directed and systemic treatments to improve response rate and quality of life. Durable remissions are uncommon, but can occur in up to 2530% of patients with the multimodality approach Consider maintenance therapy with an immunotherapy, such as interferon or bexarotene; Previously successful therapies can be used repeatedly.
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Website 201. National comprehensive cancer network http://www.nccn.org Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript. Expert Rev Dermatol. 2009;4(6):567 2009

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